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Science 15 May 1998:
Vol. 280. no. 5366, pp. 1089 - 1091
DOI: 10.1126/science.280.5366.1089
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Reports

Requirement for Atm in Ionizing Radiation-Induced Cell Death in the Developing Central Nervous System

Karl-Heinz Herzog, Miriam J. Chong, Manuela Kapsetaki, James I. Morgan, Peter J. McKinnon *

Ataxia telangiectasia (AT) is characterized by progressive neurodegeneration that results from mutation of the ATM gene. However, neither the normal function of ATM in the nervous system nor the biological basis of the degeneration in AT is known. Resistance to apoptosis in the developing central nervous system (CNS) of Atm-/- mice was observed after ionizing radiation. This lack of death occurred in diverse regions of the CNS, including the cerebellum, which is markedly affected in AT. In wild-type, but not Atm-/- mice, up-regulation of p53 coincided with cell death, suggesting that Atm-dependent apoptosis in the CNS is mediated by p53. Further, p53 null mice showed a similar lack of radiation-induced cell death in the developing nervous system. Atm may function at a developmental survival checkpoint that serves to eliminate neurons with excessive DNA damage.

K.-H. Herzog and J. I. Morgan, Department of Developmental Neurobiology, St. Jude Children's Research Hospital, 332 North Lauderdale, Memphis, TN 38101, USA.
M. J. Chong, M. Kapsetaki, P. J. McKinnon, Department of Genetics, St. Jude Children's Research Hospital, 332 North Lauderdale, Memphis, TN 38101, USA.
*   To whom correspondence should be addressed. E-mail: peter.mckinnon{at}stjude.org

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Cleavage and Inactivation of ATM during Apoptosis.
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Ataxia Telangiectasia-mutated Gene Product Inhibits DNA Damage-induced Apoptosis via Ceramide Synthase.
W.-C. Liao, A. Haimovitz-Friedman, R. S. Persaud, M. McLoughlin, D. Ehleiter, N. Zhang, M. Gatei, M. Lavin, R. Kolesnick, and Z. Fuks (1999)
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Defective Control of Apoptosis and Mitotic Spindle Checkpoint in Heterozygous Carriers of ATM Mutations.
T. Shigeta, M. Takagi, D. Delia, L. Chessa, S. Iwata, Y. Kanke, M. Asada, M. Eguchi, and S. Mizutani (1999)
Cancer Res. 59, 2602-2607
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Critical role for Atm in suppressing V(D)J recombination-driven thymic lymphoma.
M.-J. Liao and T. Van Dyke (1999)
Genes & Dev. 13, 1246-1250
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Loss of the ARF Tumor Suppressor Reverses Premature Replicative Arrest but not Radiation Hypersensitivity Arising from Disabled Atm Function.
T. Kamijo, E. van de Kamp, M. J. Chong, F. Zindy, J. A. Diehl, C. J. Sherr, and P. J. McKinnon (1999)
Cancer Res. 59, 2464-2469
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Atm Is Dispensable for p53 Apoptosis and Tumor Suppression Triggered by Cell Cycle Dysfunction.
M.-J. Liao, C. Yin, C. Barlow, A. Wynshaw-Boris, and T. van Dyke (1999)
Mol. Cell. Biol. 19, 3095-3102
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Ionizing Radiation-induced Apoptosis in Ataxia-Telangiectasia Fibroblasts. ROLES OF CASPASE-9 AND CELLULAR INHIBITOR OF APOPTOSIS PROTEIN-1.
Y. Zhang, A. Dimtchev, A. Dritschilo, and M. Jung (2001)
J. Biol. Chem. 276, 28842-28848
   Abstract »    Full Text »    PDF »
Residual Ataxia Telangiectasia Mutated Protein Function in Cells from Ataxia Telangiectasia Patients, with 5762ins137 and 7271Tright-arrowG Mutations, Showing a Less Severe Phenotype.
G. S. Stewart, J. I. K. Last, T. Stankovic, N. Haites, A. M. J. Kidd, P. J. Byrd, and A. M. R. Taylor (2001)
J. Biol. Chem. 276, 30133-30141
   Abstract »    Full Text »    PDF »
From the Cover: Abnormal development of Purkinje cells and lymphocytes in Atm mutant mice.
P. R. Borghesani, F. W. Alt, A. Bottaro, L. Davidson, S. Aksoy, G. A. Rathbun, T. M. Roberts, W. Swat, R. A. Segal, and Y. Gu (2000)
PNAS 97, 3336-3341
   Abstract »    Full Text »    PDF »
Genetic interactions between ATM and the nonhomologous end-joining factors in genomic stability and development.
J. Sekiguchi, D. O. Ferguson, H. T. Chen, E. M. Yang, J. Earle, K. Frank, S. Whitlow, Y. Gu, Y. Xu, A. Nussenzweig, et al. (2001)
PNAS 98, 3243-3248
   Abstract »    Full Text »    PDF »
Early postnatal ataxia and abnormal cerebellar development in mice lacking Xeroderma pigmentosum Group A and Cockayne Syndrome Group B DNA repair genes.
M. Murai, Y. Enokido, N. Inamura, M. Yoshino, Y. Nakatsu, G. T. J. van der Horst, J. H. J. Hoeijmakers, K. Tanaka, and H. Hatanaka (2001)
PNAS 98, 13379-13384
   Abstract »    Full Text »    PDF »


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